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This article concerns how different meaning-making strategies are used and related to each other during text reading in bilingual science teaching. A qualitative case study approach was adopted in order collect data in a public school in Sweden. Non-participant observations were made when a Turkish-speaking nineth grade (15-year-old) emergent bilingual student received additional lessons in his mother tongue in addition to regular monolingual science lessons. The purpose of the bilingual science teaching was to support the student’s meaning-making of a text about atoms. A narrative analysis shows how five meaning-making strategies were used and related to each other in various ways, depending on the context. The conversations often started with the meaning-making strategy of questioning. In some situations, relating questioning to rereading without the teacher giving any additional information resulted in the student making meaning. In other situations, this was not enough, and further meaning-making strategies were needed, namely using examples, reformulating, and translating. The bilingual science teaching enabled the student to use his whole language repertoire to make meaning of the text content. Typically, the participants read the text in Swedish and then talked about it in Turkish. However, their discussions about the meaning of scientific concepts did not follow this pattern. Scientific concepts were sometimes kept in Swedish and sometimes translated into Turkish. The translations were continuously related to everyday situations by using examples and reformulation as meaning-making strategies. This detailed analysis of the strategies used contributes to an increased understanding of the meaning-making process in text reading during bilingual science teaching. Educators might draw on these findings to support emergent bilingual students in similar situations.

In science education research, there is a growing body of studies focusing on the role of multiple representations in pupils’ learning. This study is based on a social semiotic perspective and in the analysis, there is a special focus on how the content is conveyed and how relations are created through interaction between teachers/pupils and the infrared camera and between teachers and pupils. We report the results from a pilot study involving one teacher’s work with thermal phenomena in grade 6. A class of 45 primary pupils, divided in 4 groups. Overall, we describe findings from three lessons involving experiments situated in pupils’ everyday experiences of thermal phenomena. In the analysis, we focus on two groups of pupils (N = 25) and data are generated from three lessons by video and audio recordings. With the help of the infrared camera, the pupils manage to represent heat as a process. The infrared camera provides a visual interface for a shared point of reference and is an important semiotic resource for stimulating verbal communication between pupils and between pupils and teachers.

Worksheets are common in science classrooms with an aim to support pupils’ meaning-making, e.g., for guiding them in performing hands-on activities and documenting their experiences of such activities. Yet, there have been few systematic studies of pupils’ disciplinary representations in worksheets. Drawing on systemic functional linguistics, we have analyzed fifth grade pupils’ (age 10–11) multimodal texts in worksheets (n = 25) when they were working with shadow formation as part of their regular classroom activities. In the worksheets they were asked to first explain in writing why or why not a shadow was formed and then explain shadow formation through a drawing. At an overall level, we found that a majority of the pupils managed to express in writing why a shadow is formed, though it appeared to be more challenging for them to explain why a shadow is not formed. In their drawings, quite a few pupils managed to include several key aspects of shadow formation, at least when combining image with writing. For all tasks, the explanatory parts of the pupils’ responses were often implicit. Based on our results, we suggest that pupils may benefit from teaching practices that integrate a parallel focus on form and content as a way to raise their awareness of, for instance, the affordances of different resources and how explanations can be structured. Such practices may support pupils to be able to consider and choose appropriate resources in their disciplinary texts.

I de senaste styrdokumenten för fritidshem framgår att fritidshem ska bedriva undervisning samt att det finns ett kompletterande uppdrag där verksamheten ska planeras och genomföras så att eleverna tränar vissa förmågor. Men undervisning är inte detsamma som lärande. Om undervisningen ska bidra till lärande måste fritidsläraren vara medveten om hur elever lär sig, besitta vissa ämneskunskaper samt bedriva en undervisning som ökar elevers förståelse. Denna artikel baseras på ett empiriskt material som samlades in till en studie inom ramen för en masterkurs i yngre barns lärande i naturvetenskap, teknik och hållbar utveckling.

This study is part of a larger project with the general aim of developing the ability of preschool teachers to reflect critically on questions, topics and theories related to different understandings of death(s). The article is based on three focus-group interviews with a focus on how preschool teachers reflect on what, how, why and when they teach about death and death-related issues. The results show that preschool teachers consider that it is important in early childhood education to teach about death because death is a fundamental aspect of life in daily reality, and they consider it to be their task to comfort a child in grief, as well as care for the well-being of the group. However, much of the time, they avoid teaching about biological death relative to concrete goals that the children are to achieve in understanding what death implies. Instead, they use child-responsive, improvisational teaching that is intended to calm and comfort the children. The content of the teaching arises at the intersection of expert knowledge in talking about death as an irreversible outcome of natural processes and the preschool teachers own beliefs and ideas about death, dying and an afterlife. As a consequence, the biological conceptions of death coexist with the teachers own beliefs in an afterlife, reflecting a dualistic thinking within which culturally constructed beliefs coexist with biological views. Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-03839]

The aim of the present study is to advocate the use of a participatory action research programme, the Formative Scaffolding Programme (FSP), in mathematics. The FSP’s main structure is presented as well as an implementation of a class intervention, with the aim of exploring the FSP test cycle’s virtues in a social science class in a Swedish upper-secondary school. The motivations for the FSP’s development were to enhance students’ awareness of their mathematical proficiency, alter the level and strength of their self-efficacy, foster self-regulated learning (SRL), reduce and prevent mathematics-related anxiety, and visualise the learning process in mathematics. The primary findings of the study were there was a resemblance between the FSP setting and SRL phases, and that participation in the test cycle altered the level and strength of students’ self-efficacy and fostered self-regulation in a mathematics test situation. The benefits of working in a formative scaffolding manner indicate that it is worth implementing the FSP on a larger scale. The study is an example of how students can engage in transforming classroom practice and be radical agents of change.

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.

Varför är det mer angeläget och accepterat att jobba tvärvetenskapligt med estetiska lärprocesser och naturvetenskapliga ämnen för yngre barns lärande i skolans tidigare år än med äldre elever? Tillsammans med forskakollegor har vi i våra studier visat hur våra sinnliga kroppsliga erfarenheter har betydelse för lärande för alla åldrar.

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism., NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.

Science education research has long taken an interest in how we may make full use of analogies and metaphors in science teaching. Further, more recently, the role of implicit, conceptual metaphors in connecting abstract conceptual knowledge to concrete embodied experiences has been recognised. The textbook plays a central role in upper secondary teaching, as it is, together with the teacher, a source of knowledge for the students. We have analysed the use of analogies, and explicit and implicit metaphors in two Swedish upper secondary chemistry textbook, and interviewed two of the authors of the textbooks. Abstract states and processes were found to be construed by means of the Object-Event and Location-Event Structure metaphors. Explicit metaphors and analogies were presented, but the comparisons were not always elaborated sufficiently in order to guide the students’ interpretations and avoid possible misunderstandings.

This study investigates primary school children’s (7-8 year-old, N = 25) ideas of mixing of marbles and of heat, expressed in small-group predict-observe-explain exercises, and drawings representing the children’s own analogies in a classroom setting. The children were typically found to predict that marbles of two different colours would mix when rocked back and forth on a board. This idea of mixing is slightly more advanced than previously reported in the literature. The children’s ideas of heat included reference to warm objects, their own bodies when exercising, and the process of one warm solid object heating another object in direct contact. In addition, through scaffolding, some of the children expressed a substance view of heat. Finally, the potential and challenges in probing children’s ideas through a combination of data collection techniques in a classroom setting are reflected upon. Key words: heat, mixing, children’s ideas, primary school, classroom setting.

Med hjälp av värmekameror framträder lejonen på Serengeti tydligt på kilometers håll i natten på BBC:s senaste filmer och läckande fjärrvärmeledningar kan numera upptäckas från helikopter. Det kan låta som science fiction, men den snabba teknikutvecklingen inom detta område gör att vi nu kan ”göra det osynliga synligt” även i det naturvetenskapliga klassrummet.

β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell stemness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.

Integration of technology, social learning and scientific models offers pedagogical opportunities for science education. A particularly interesting area is thermal science, where students often struggle with abstract concepts, such as heat. In taking on this conceptual obstacle, we explore how hand-held infrared (IR) visualization technology can strengthen students’ understanding of thermal phenomena. Grounded in the Swedish physics curriculum and part of a broader research programme on educational uses of IR cameras, we have developed laboratory exercises around a thermal storyline, in conjunction with the teaching of a heat-flow model. We report a narrative analysis of how a group of five fourth-graders, facilitated by a researcher, predicts, observes and explains (POE) how the temperatures change when they pour hot water into a ceramic coffee mug and a thin plastic cup. Four chronological episodes are described and analysed as group interaction unfolded. Results revealed that the students engaged cognitively and emotionally with the POE task and, in particular, held a sustained focus on making observations and offering explanations for the scenarios. A compelling finding was the group’s spontaneous generation of multiple "what-ifs" in relation to thermal phenomena, such as blowing on the water surface, or submerging a pencil into the hot water. This was followed by immediate interrogation with the IR camera, a learning event we label instant inquiry. The students’ expressions largely reflected adoption of the heat-flow model. In conclusion, IR cameras could serve as an access point for even very young students to develop complex thermal concepts. As per the Springer Copyright agreement, a Postprint of the Accepted Manuscript (PDF) is available via the personal website of the author(s) at the following link:http://webstaff.itn.liu.se/~konsc/Haglund_Jeppsson_Schonborn_2015_Postprint ThermalVis

Infrared cameras can be used in science education. The technology suits open-ended thermodynamics laboratory exercises in higher education. School children engage in instant inquiry of thermal phenomena.

Various features of scientific discourse have been characterized in the science education literature, and challenges students face in appropriating these features have been explored. Using the fram ...

Using self-generated analogies has been proposed as a method in a constructivist tradition for students to learn about a new subject, by use of what they previously know. We report on a group exercise on using self-generated analogies to make sense of two thermodynamic processes, reversible adiabatic expansion and free adiabatic expansion of an ideal gas. The participants (N = 8) were physics preservice teacher students at the fourth year of the teacher education program. A main finding was that work with self-generated analogies tended to be accompanied by the students assuming ownership for their learning, manifested in terms of actions of choice and control and the use of exploratory talk. Consequently, several self-generated analogies were elaborated and developed to a high-order relational structure. However, we also found that with the use of self-generated analogies in science teaching follows the risks of developing idiosyncratic explanations of the encountered phenomena or getting stuck in overly complex comparisons. Självgenererade analogier har förts fram som en metod i en konstruktivistisk tradition för att elever och studenter ska kunna lära sig något nytt genom att relatera till vad de redan vet. Vi redogör här för en gruppövning där självgenererade analogier användes för att förstå två termodynamiska processer: reversibel adiabatisk expansion, respektive fri adiabatisk expansion av en ideal gas. Åtta (N = 8) lärarstudenter på fjärde året av utbildningen med inriktning mot fysik på gymnasiet deltog i studien. Ett viktigt resultat var att vid arbete med självgenererade analogier tenderade studenterna att ta ägandeskap för sitt lärande, vilket tog sig uttryck i handlingar såsom aktiva val, kontroll över processen och explorativ dialog. Som en följd utvecklades flera av de självgenererade analogierna till ett stort strukturellt djup. Samtidigt såg vi att vid skapande av egna analogier löper studenter risken att utveckla egna förklaringar av de studerade fenomenen som inte svarar mot dem inom vetenskapen eller snärja in sig i alltför komplexa jämförelser.

This exploratory study in a classroom setting investigates first graders (age 78 years, N = 25) ability to perform analogical reasoning and create their own analogies for two irreversible natural phenomena: mixing and heat transfer. We found that the children who contributed actively to a full-class discussion were consistently successful at making analogical comparisons between known objects provided by a researcher and that some of the children could come up with their own analogies for the abstract natural phenomena with which they interacted. The use of full-class and small-group settings, shared laboratory experiences of the phenomena and childrens drawings as different kinds of scaffolding was found to be helpful for the childrens analogical reasoning. As an implication for science education, self-generated analogies are put forward as a potential learning tool within a constructivist approach to education.

A challenge in the teaching of entropy is that the word has several different senses, which may provide an obstacle for communication. This study identifies five distinct senses of the word ‘entropy’, using the Principled Polysemy approach from the field of linguistics. A semantic network is developed of how the senses are related, using text excerpts from dictionaries, text books and text corpora. Educational challenges such as the existence of several formal senses of entropy and the intermediary position of entropy as disorder along the formal/non-formal scale are presented using a two-Dimensional Semiotic/semantic Analysing Schema (2-D SAS).

The presence of beta-amyloid plaques in brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([(11)C]-2-(3-fluoro-4-methylamino-phenyl)-benzothiazol-6-ol) (PIB) binds selectively to beta-amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal-to-background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol) was found to have high affinity for amyloid fibrils in vitro (K(d): 8.4 +/- 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid-beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [(3)H]AZD2184 and [(3)H]PIB are mutually displaceable, [(3)H]AZD2184 displays a higher signal-to-background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [(3)H]AZD2184 and 0.8 for [(3)H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [(3)H]AZD2184 and antibodies to human beta-amyloid labeled identical structures. In vivo administration of [(3)H]AZD2184 to APP/PS1 mice further showed that [(3)H]AZD2184 labels amyloid deposits with low non-specific background binding. Taken together, the pre-clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that (11)C-labeled AZD2184 is a potential radioligand for PET-visualization of beta-amyloid deposits in the living human brain.

Science education research suggests that our everyday intuitions of motion and interaction of physical objects fit well with how physicists use the term “momentum”. Corpus linguistics provides an easily accessible approach to study language in different domains, including everyday language. Analysis of language samples from English text corpora reveals a trend of increasing metaphorical use of “momentum” in non-science domains, and through conceptual metaphor analysis, we show that the use of the word in everyday language, as opposed to for instance “force”, is largely adequate from a physics point of view. In addition, “momentum” has recently been borrowed into Swedish as a metaphor in domains such as sports, politics and finance, with meanings similar to those in physics. As an implication for educational practice, we find support for the suggestion to introduce the term “momentum” to English-speaking pupils at an earlier age than what is typically done in the educational system today, thereby capitalising on their intuitions and experiences of everyday language. For Swedish-speaking pupils, and possibly also relevant to other languages, the parallel between “momentum” and the corresponding physics term in the students’ mother tongue could be made explicit..

Thermal cameras offer real-time visual access to otherwise invisible thermal phenomena, which are conceptually demanding for learners during traditional teaching. We present three studies of students’ conduction of laboratory activities that employ thermal cameras to teach challenging thermal concepts in grades 4, 7 and 10–12. Visualization of heat-related phenomena in combination with predict-observe-explain experiments offers students and teachers a pedagogically powerful means for unveiling abstract yet fundamental physics concepts. As per the IOP Publishing Copyright agreement, a Postprint of the Accepted Manuscript(PDF) is available via the personal website of the author(s) at the following link:http://webstaff.itn.liu.se/~konsc/Haglund_Jeppsson_Hedberg_Schonborn_2015_Postprint ThermalVis

We introduce here a special issue of this journal on the theme of ‘Conceptual Metaphor and Embodied Cognition in Science Learning'. The idea for this issue grew out of a symposium that we organized...

Many studies have previously focused on how people with different levels of expertise solve physics problems. In early work, focus was on characterising differences between experts and novices and a key finding was the central role that propositionally expressed principles and laws play in expert, but not novice, problem-solving. A more recent line of research has focused on characterising continuity between experts and novices at the level of non-propositional knowledge structures and processes such as image-schemas, imagistic simulation and analogical reasoning. This study contributes to an emerging literature addressing the coordination of both propositional and non-propositional knowledge structures and processes in the development of expertise. Specifically, in this paper, we compare problem-solving across two levels of expertise — undergraduate students of chemistry and Ph.D. students in physical chemistry — identifying differences in how conceptual metaphors (CMs) are used (or not) to coordinate propositional and non-propositional knowledge structures in the context of solving problems on entropy. It is hypothesised that the acquisition of expertise involves learning to coordinate the use of CMs to interpret propositional (linguistic and mathematical) knowledge and apply it to specific problem situations. Moreover, we suggest that with increasing expertise, the use of CMs involves a greater degree of subjective engagement with physical entities and processes. Implications for research on learning and instructional practice are discussed.

Nature 508, 215–221 (2014); doi:10.1038/nature13181 In this Article, the structure of compound TH650 (4) in Fig. 4a was drawn incorrectly; the correct structure is shown as Fig. 1 to this Corrigendum. Preparative, spectroscopic and biological data associated with this compound are as reported in theArticle, and the error does not influence any of the reported data or interpretations.

Use of self-generated analogies has been proposed as a method for students to learn about a new subject by reference to what they previously know, in line with a constructivist perspective on learning and a resource perspective on conceptual change. We report on a group exercise on using completion problems in combination with self-generated analogies to make sense of two thermodynamic processes. The participants (N = 8) were preservice physics teacher students at the fourth year of the teacher education program. The students experienced challenges in accounting for the constant entropy in reversible, adiabatic expansion of an ideal gas and the constant temperature in free, adiabatic expansion of an ideal gas. These challenges were found to be grounded in the students’ intuitive understanding of the phenomena. In order to come to terms with the constant entropy in the first process, the students developed idiosyncratic explanations, but these could by properly adjusted given suitable scaffolding. In contrast, the students by themselves managed to make sense of the constant temperature in free expansion, by use of microscopic explanatory models. As a conclusion, self-generated analogies were found to provide a useful approach to identifying challenges to understanding among students, but also for the students to come to terms with these challenges. The results are discussed against a background of different perspectives on the issue of conceptual change in science education.

Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC(50) 160 pm in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aβ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

progressors respectively) (P

BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.

Purpose The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer’s disease (AD). Methods In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. Results AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Conclusion Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. Electronic supplementary material The online version of this article (doi:10.1007/s00259-012-2322-6) contains supplementary material, which is available to authorized users.